BRPI0619306A2 - pharmaceutical or cosmetic composition, use of a composition and processes for making a composition - Google Patents

Abstract

PHARMACEUTICAL OR COSMETIC COMPOSITION, USE OF A COMPOSITION AND PROCESSES FOR MANUFACTURING A COMPOSITION The present invention deals with a pharmaceutical or cosmetic composition comprising at least one hydrophilic phase, at least one lipophilic phase and at least one active principle, which is present in solubilized form in each of these phases. The present invention also deals with the process of making that composition.

Description

"PHARMACEUTICAL OR COSMETIC COMPOSITION, USE OF A COMPOSITION, AND PROCESSES FOR MANUFACTURING A COMPOSITION"

Field of the Invention

The present invention relates to a composition for pharmaceutical or cosmetic use, comprising at least two stages in which the same active ingredient is solubilized, as well as the manufacturing process of such composition.

Background of the Invention

Emulsions are commonly manufactured and used in the pharmaceutical or cosmetic field, the active ingredient of which is solubilized in only one phase, be it a hydrophilic phase or a lipophilic phase.

Now the solubilization of an active principle in only one phase is not without its problems. Indeed, the maximum concentration of the active ingredient, solubilizable in one phase, may be lower than the therapeutically effective concentration in the condition (s) to be treated.

Migration phenomena of the active principle from its solvent phase to the other phase may still appear and cause its recrystallization. In this case, recrystallization can be particularly problematic when the active ingredient has irritating potential. Irritation problems may be encountered due to direct contact of the crystals with the skin during formulation application.

These recrystallization problems can manifest themselves when the active principle is dispersed in a very weakly solvent phase of this active principle.

Active in the dispersed form is an active principle in the form of solid particles suspended in a given vehicle. Preferably, the dispersed particles are visible to the naked eye or by light microscopy such as cross polarization microscopy. Thus, the size of the dispersed particles is preferably greater than or equal to 1 micron.

To improve skin penetration, US 6,491,396 proposes an oil-in-water (O / W) emulsion in which the active principle, vitamin D3-derived maxacalcitol, is present in the lipophilic phase and / or the hydrophilic phase. . Maxacalcitol is then in a solubilized state in the lipophilic phase, and in a dispersed state in the hydrophilic phase.

This emulsion is not entirely satisfactory. In particular, the drawbacks associated with dispersing in a vehicle are manifold. Thus, when a certain concentration is exceeded, aggregate and dispersion heterogeneity problems may arise. Moreover, the search for dispersing agent adapted to the active ingredient is not always easy. The particle size of the active ingredient must also be given close attention depending on the application site and the biological target to be achieved.

Moreover, the presence in the formulation of the active principle in two different states (solubilized in one phase and dispersed in the other) may prove detrimental. In fact, the dispersed active ingredient constitutes a recrystallization germ and can cause a problem of crystalline growth, a phenomenon difficult to control and harmful to the formulation in terms of physical stability and therapeutic efficacy.

The inventors have now revealed that it is possible to solve the problems mentioned above by solubilizing the active principle in the two stages of the composition. In particular, they have surprisingly shown that while the active ingredient is solubilized in both phases, the composition is physically stable and allows to achieve a higher overall concentration of the therapeutically effective active ingredient.

By "physical stability" of the composition according to the present invention is meant in particular a composition which does not have a phase lag after storage for three months at 4 ° C, room temperature and 40 ° C. According to the present invention, another parameter of physical stability observed is in particular the absence of recrystallization phenomenon at room temperature and at 4 ° C for three months.

In fact, at the therapeutically effective concentration, no phenomenon of recrystallization of the active principle was observed after storage of the formulations for 3 months at room temperature and at 4 ° C.

Throughout the present text, the active principle in solubilized form is understood to mean a dispersion of the molecular state in a liquid, without any crystallization of the active being visible to the naked eye, even through the cross-polarized optical microscope, or by of other more precise techniques such as electron microscopy. Preferably, the active principle particles have a size of less than 1 nm.

Preferably according to the present invention, the active principle in solubilized form means a dispersion in the molecular state in a liquid where there is no crystallization of the active visible to the naked eye or under the optical microscope.

Description of the Invention

The present invention therefore deals with a pharmaceutical or cosmetic composition comprising at least two phases of distinct polarities, the same active ingredient present in the solubilized form in each of these phases, and the manufacturing process of such composition.

The present invention therefore relates to a pharmaceutical or cosmetic composition comprising at least one hydrophilic phase, at least one lipophilic phase, and at least one active ingredient, which is present in solubilized form in at least said hydrophilic phase and at least said lipophilic phase.

Preferably the composition is an emulsion.

Preferably, the composition comprises a hydrophilic phase (and only one) and a lipophilic phase (and only one).

According to the present invention, solubilization of the active principle in the two phases of the composition offers multiple advantages.

It can allow modulating the release of the active ingredient. For example, in an O / W emulsion (oil in water), the active ingredient fraction that is solubilized in the outer phase of the emulsion (here the hydrophilic phase) is released before the solubilized fraction in the inner phase (here the lipophilic phase). . This deferred release of the active principle thus gives the formulation a reservoir role for the active principle.

Solubilization at different stages also reduces irritation problems when the active ingredient is potentially irritating. On the one hand, the phenomenon of recrystallization of the active principle is considerably reduced, on the other hand, the modulation of its release allows to significantly improve the tolerance of a formulation for topical use avoiding a rapid accumulation of the active principle in the skin layers, responsible for the problems of irritation. Solubilization of the active principle in the two phases of the composition allows to achieve a higher concentration of active principle than if it had been solubilized in only one phase. This concentration of solubilized active ingredient in only one phase is often much lower than the therapeutically effective concentration. Solubilization of the active ingredient at different stages of the composition allows sufficient concentration to be achieved to achieve recognized efficacy in the condition (s) to be treated.

The Active Principles

Any active ingredient may be used as long as it is soluble and is in the same molecular state in each of the emulsion phases. Indeed, it is known that certain active ingredients may be present in the solubilized state at the different stages of an emulsion, but in the sallified form in one, and in the unsalified form in the other. However, the active principle solubilized in the two phases of the composition according to the present invention is present in the same molecular state.

Furthermore, in the composition according to the present invention, the active ingredient is present in the same physical state in the two phases of the composition. In fact, according to the present invention, the active ingredient is solubilized in each of the phases of the composition and in no case dispersed in either of the two phases.

The molecules used as active principle in such compositions therefore preferably have a particular solubility profile described below.

They have sufficient solubility in water or polar compounds classically used in the pharmaceutical or cosmetic field, preferably in topical formulations.

This solubility in the polar media allows its solubilization in the hydrophilic phase of the composition.

Moreover, these molecules have sufficient solubility in lipophilic excipients commonly used in the pharmaceutical or cosmetic field, preferably in topical formulations, which allow their solubilization in the lipophilic phase of the emulsion.

By sufficient solubility is meant a solubility of from 0.005% to 1%, preferably from 0.01% to 0.5% by weight of active relative to the total weight of the solvent (water, polar compounds, lipophilic excipients). By "soluble" is meant the characteristic of certain solid bodies to form solutions when they are introduced into an appropriate solvent. Different parameters may influence the solubility of a molecule in the solvent considered. Thus, molecular weight, melting point, chromatographic purity, crystalline structure, and also chemical structure, and in particular the nature of the functional groups and the hydrophilic or lipophilic parts, contribute to their solubility profile.

The parameters for characterizing the solubility profile of a molecule are in particular the solubility parameter and the Pog of the molecule.

The solubility parameter represents the set of solvent / solute molecular interactions, ie dispersion forces, polar interactions and hydrogen bond type interaction.

The Hansen method, known to the person skilled in the art, allows the determination of the overall solubility parameter of a molecule theoretically (using the group contribution method applied to the molecule) and experimentally by evaluating the solubility of that molecule in solvents. whose overall solubility parameter has been determined.

The interest of this method is to establish a list of potential solvents for the studied molecule.

These potential solvents have a solubility parameter close to that of the molecule.

The overall solubility parameter of the molecules used in the compositions of the present invention is between 10 and 40, preferably between 15 and 30 and more preferably between 18 and 24.

Another parameter that allows you to evaluate the solubility of a molecule is its Yog Ρ. The Yog P of a molecule is represented by the relationship of its solubility in octanol and its solubility in water.

This parameter is important for molecules used in the topical pathway.

In fact, this octanol / water sharing is representative of the sharing of the molecule during its application to the skin, sharing between the hydrophilic parts (cells) on one side and lipophilic (intercellular cement) parts of the skin on the other side.

The Yogarithm of the sharing coefficient (indicated by the reference Yog P) then allows to know its polarity. In fact, the higher the P1 Iog the more the molecule will have a lipophilic character. Conversely, the lower this value, the more the molecule will have a polar character. The molecules usable in the present invention have a Pog of from 2 to 6, and preferably from 4 to 5, so that they can be solubilized in the hydrophilic phase as in the lipophilic phase of the composition.

In addition, the molecules used as active ingredient are preferably chemically stable in each of the phases in which they are solubilized.

Steroidal anti-inflammatory agents, antifungal agents, antiparasitics, nuclear receptor modulators, and sex steroid hormones are non-exhaustive examples of molecules that possess these physicochemical properties.

Steroidal anti-inflammatory agents include mainly corticosteroids such as beclomethasone, betamethasone, clobetasol, cortisone, desonide, dexamethasone, fluochloronide, fluocinolonacetonide, fluocinonide, fludroxocortide, , halcinonide, hydrocortisone, methylprednisolone, prednisone, prednisone, triamcinolone, triamcinolonacetonide or mixtures thereof.

Among the antifungal agents may be cited mainly amorolfine, clotrimazole, fluconazole, ketoconazole, miconazole or tolnaftate.

Antiparasitic agents include mainly ivermectin and more generally the avermectin family.

Sex steroid hormones usable in the present invention include DHEA or dehydroepiandrosterone, as well as their precursors and chemical and / or biological derivatives.

Nuclear receptor modulating agents include, for example, retinoids and their analogs, PPAR (peroxisome proliferation-activated receptor) receptor modulating compounds, and vitamin D and its analogs or derivatives.

Retinoids include, for example, retinoic acid or tretinoin, 13-cis retinoic acid or isotretinoin, retinol, acitretin, adapalene, or mixtures thereof.

Among PPAR receptor modulating compounds, particular mention may be made of thiazolidinediones and derivatives.

By vitamin D analogues are meant different forms of vitamin D such as, for example, vitamin D2 or vitamin D3. By "vitamin D derivatives" is meant compounds having biological properties analogous to those of vitamin D, in particular transactivating properties of the vitamin D response elements (VDRE), such as an agonist or antagonist activity against vitamin D receptors. D or its derivatives. Such compounds are generally not natural vitamin D metabolites. They are in particular synthetic compounds which comprise the vitamin D backbone with side chain modifications and / or which also comprise backbone modifications themselves. Vitamin D-derived compounds useful in accordance with the present invention thus comprise structural analogues, for example bioaromatics.

Illustrative of these vitamin D1 derivatives may be cited in particular calcipotriol, calcitriol or 1,25 dihydroxyvitamin D3, doxercalciferol, secalcitol, maxacalcitol, seocalcitol, tacalcitol, paricalcitol, falecalcitriol, 1 24S-dihydroxyvitamin D2, 1 (S), 3 (R) -dihydroxy-20 (R) - [((3- (2-hydroxy-2-propyl) phenyl) methoxy) methyl] - 9,10-seco-pregna5 (Z), 7 (E), 10 (19) -triene, mixtures and derivatives thereof. According to a particular embodiment, derivatives of

Vitamin Ds preferably used herein are described in WO 00/26167. These are structural analogues of vitamin D that show selective activity on cell proliferation and differentiation without being hypercalcemic.

Such compounds may be represented by the following general formula (I):

<formula> formula see original document page 10 </formula>

in which

- R1 represents a hydrogen atom, a methyl radical or a (CH2) W-OR7 radical,

- R2 represents a radical - (CH2) n-OR81 where n, R7 and R8 have the meanings given below,

- X-Y represents a bond chosen from the indicated bonds of formulas (a) to (d) which can be read from left to right or in reverse:

<formula> formula see original document page 10 </formula>

R9 and W have the meanings given below,

- R3 represents the vitamin D2 or vitamin D3 chain, the dotted lines represent the binding linking the chain to the benzene cycle shown in Figure (I) 1 or

-R3 represents a chain having from 4 to 8 carbon atoms substituted by one or more hydroxyl groups, and the hydroxyl groups may be protected as acetoxy, methoxy or ethoxy, trimethylsilyloxy, tertiary butyl dimethylsilyloxy, tetra -hydropyranyloxy and possibly further:

- substituted by one or more lower alkyl or cycloalkyl groups and / or

- substituted by one or more halogen atoms, and / or

- replaced by one or more CF3 groups, and / or

- wherein one or more carbon atoms in the chain are substituted by one or more oxygen, sulfur or nitrogen atoms, and nitrogen atoms may optionally be substituted by lower alkyl radicals, and / or

- wherein one or more single bonds in a chain are replaced by one or more double and / or triple bonds,

- and R3 is positioned in the benzene cycle at para or goal of an X-Y bond,

- R4, R5 and R61 are identical or different, represent a hydrogen atom, a lower alkyl radical, a halogen atom, a radical - OR101 a polyether radical, and

R10 has the meaning given below,

- and η is 0,1 or 2,

- R 7 and R 8 are identical or different, represent a hydrogen atom, an acetyl radical, a trimethylsilyl radical, a terciobutyldimethylsilyl radical, a tetrahydropyranyl radical,

- R 9 represents a hydrogen atom or a lower alkyl radical,

- W represents an oxygen, sulfur atom, a radical - CH2- or a radical

- NH- which may optionally be substituted by a lower alkyl radical,

-R10 represents a hydrogen atom or a lower alkyl radical, as well as isomers and geometrics of said compounds of formula (I) as well as their salts if XY represents a bond of formula (a) and W represents a -NH radical - optionally substituted by a lower alkyl radical.

By the term "lower alkyl radical" is meant a straight or branched alkyl radical having from 1 to 6 carbon atoms.

Among the compounds of formula (I) which may be used in the compositions of the present invention may be mentioned in particular:

1. 6- [3- (3,4-bishydroxymethyl benzyloxy) phenyl] -2-methylhepta-3,5-dien-2-ol,

2. 7- [3- (3,4-bis-hydroxymethyl-phenoxymethyl) -phenyl] -3-ethyl-octan-3-ol,

3. 7- {3- [2- (3,4-Bishydroxymethyl-phenyl) -ethyl] -phenyl} -3-ethyl-octa-4,6-dien-3-ol,

4. 6- {3- [2- (3,4-Bishydroxymethyl-phenyl) -ethyl] -phenyl} -2-methyl-hepta-3,5-dien-2-ol,

5. 7- {3- [2- (3,4-Bishydroxymethyl-phenyl) -vinyl] -phenyl} -3-ethyl-octa-4,6-dien-3-ol,

6. 7- [3- (3,4-Bishydroxymethyl-benzyloxy) phenyl] -3-ethyl-3-octanol,

7. 4E, 6E) -7- [3- (3,4-Bis-hydroxymethyl-benzyloxy) -phenyl] -3-ethyl-octa-4,6-dien-3-ol,

8. (4E, 6E) -7- [3- (3,4-Bis-hydroxymethyl-benzyloxy) -phenyl] -3-ethyl-one-4,6-dien-3-ol,

9. (E) -7- [3- (3,4-Bishydroxymethyl-benzyloxy) -phenyl] -3-ethyl-oct-4-en-3-ol,

10. (E) -7- [3- (3,4-Bishydroxymethyl-benzyloxy) -phenyl] -3-ethyl-oct-6-en-3-ol,

11. (E) -7- [3- (3,4-Bis-hydroxymethyl-benzyloxy) -phenyl] -3-ethyl-oct-6-en-4-yn-3-ol,

12. (E) -7- [3- (3- (3,4-Bis-hydroxymethyl-phenoxymethyl) -phenyl] -3-ethyl-octa-4,6-dien-3-ol

13. (E) -7- [3- (3,4-Bishydroxymethyl-phenoxymethyl) -phenyl] -3-ethyl-non-6-en-3-ol,

14. (E) -7- {3 - [(3,4-Bis-hydroxymethyl-benzyl) -methylamino] -phenyl} -3-ethyl-oct-6-en-3-ol, and

15. 7- [3- (3,4-Bishydroxymethyl-benzyloxy) -phenyl] -3-ethyl-7-methyl-octan-3-ol.

In particular, the pharmaceutical active ingredient incorporated in the composition according to the present invention is (4E, 6E) -7- [3- (3,4-bis-hydroxymethyl-benzyloxy) -phenyl] -3-ethyl-nona-1-one. 4,6-dien-3-ol.

The Composition of the Present Invention The composition of the present invention is preferably in the form of an emulsion.

"Emulsion" according to the present disclosure means a composition comprising at least two phases of distinct polarities, wherein at least one phase is dispersed in another phase.

Compositions of the present invention are "simple" emulsions such as water in oil (W / O), oil in water (O / W), silicone water, silicone glycol, or cream gels (oil phase). dispersed in an aqueous phase by a non-surfactant polymeric emulsifier) or triple emulsions (eg W / O / W, O / W / O).

The composition according to the present invention is preferably an emulsion having at least one hydrophilic phase and at least one lipophilic phase, or at least one glycolic or hydroglycolic phase and at least one lipophilic phase.

The proportions of each phase are chosen according to the active ingredient and its solubility in the hydrophilic phase and the lipophilic phase in order to achieve the therapeutically effective active ingredient concentration for the condition (s) to be treated.

According to the present invention, the hydrophilic phase represents 10 to 90% (expressed by weight relative to the total weight of the composition), preferably 10 to 45% of the composition.

According to the present invention, the lipophilic phase represents 10 to 90% (expressed by weight relative to the total weight of the composition), preferably 15 to 50% by weight of the composition.

Hydrophilic Phase of Composition

The hydrophilic phase compounds are chosen according to the solubility profile of the active ingredient to be solubilized therein.

The hydrophilic phase comprises at least one hydrophilic solvent, which may be chosen in particular from water or a mixture of water and alcohol (s) with C1 to C4, such as ethanol, isopropanol or butanol (hydroalcoholic solution), as well as glycols or mixtures thereof, in particular glycol / water (hydroglycolic phase) mixtures. In addition, it should be noted that the hydrophilic solvent may be exclusively glycolic. An example of emulsions using this hydrophilic phase is a Glycol / Silicone emulsion. Preferably at least one hydrophilic phase of the composition according to the present invention is a glycolic or hydroglycolic phase.

Preferably at least one hydrophilic phase of the composition according to the present invention comprises the active ingredient solubilized in at least one hydrophilic solvent, and at least one other hydrophilic compound. Such another compound may be another hydrophilic solvent, or any other compound introduced into the hydrophilic phase.

Glycols usable in the present invention include alkylenes or polyalkylene glycols. Non-limiting examples include C1-6 alkylene and polyalkylene glycols such as ethylene glycol, polyethylene glycols (2 to 20 monomers), propylene glycol, dipropylene glycol, butylane glycol, pentylene glycol, hexylene glycol.

Preferably, the glycols used according to the present invention are chosen from propylene glycol or PEG 400.

Lipophilic Stage of Composition

The lipophilic phase compounds are also chosen according to the solubility profile of the active ingredient to be solubilized therein.

By lipophilic phase is meant a phase which contains, on the one hand, the active ingredient, and on the other hand exclusively lipophilic compounds. Thus, this phase comprises no hydrophilic compound.

The lipophilic phase comprises at least one lipophilic solvent, which may be an optionally volatile oil. Preferably, it comprises at least one (possibly volatile) solvent oil of the molecule and / or a wax.

Preferably at least one lipophilic phase of the composition according to the present invention comprises the active ingredient solubilized in at least one lipophilic solvent, and at least one other lipophilic compound. Such another compound may be another lipophilic solvent, or any compound introduced into the lipophilic phase. In accordance with the present invention, the wax may be an animal, vegetable, mineral or synthetic wax.

Among animal waxes one can in particular cite beeswax, whale wax. Vegetable waxes include carnauba, candelilla, ouricuri waxes, cork fiber waxes, sugar cane waxes, and Japanese waxes. in particular paraffin waxes, microcrystalline waxes, lignite waxes and ozoquerites. Finally, synthetic waxes include polyethylene waxes and waxes obtained by FishereTropsch synthesis.

Among the oils (lipophilic solvent) usable in the present invention are mink oil, turtle oil, soybean oil, grape seed oil, sesame oil, corn oil, rapeseed, sunflower oil, cottonseed oil, avocado oil, olive oil, castor oil, jojoba oil, peanut oil; hydrocarbon oils such as paraffin oils, squalane, petroleum jelly; esters such as isopropyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, isononyl isononate, cetearyl isononate, 2-ethylhexyl palmitate, 2-hexyl decyl laurate, 2-octyl palmitate deciles, 2-octyl dodecyl myristate, 2-diethylhexyl succinate, diisostearyl malate, 2-octyl dodecyl lactate, glycerin triisoestearate, capric caprylic triglyceride, alkyl benzoate with C12-15, oils are perfluorinated and / or organofluorinated; superior fatty acids such as myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, isostearic acid, higher fatty alcohols such as kethanol, stearyl alcohol, oleic alcohol, Guerbet alcohols such as hexyl decanol, octyl dodecanol. The oils usable according to the present invention may also be linear siloxane-like silicon oils and more preferably hexamethyldisiloxane. By way of example, the product marketed by Dow Corning, DC Fluid® 0.65cSt.

The lipophilic phase components according to the present invention are preferably selected from isopropyl palmitate, caprylic / capric triglyceride (Miglyol 812), C12-C15 alkyl benzoate (Finsolv TN), cetearyl isononanoate (Cetiol SN ), octyl dodecanol (Eutanol G)

Surfactants are also advantageously used to obtain a stable emulsion. They are also preferably used to obtain very fine emulsions, particularly in the case of multiple emulsions.

Surfactants (emulsifiers or surfactants) are natural or synthetic substances formed of a hydrophilic or polar part and a lipophilic or support part. They are amphiphilic molecules since they have double polarity. Surfactants are characterized by their HLB. The surfactants are placed at the interface of the hydrophilic and lipophilic phases. The HLB value of the surfactant guides the direction of the emulsion.

Preferably, the emulsion composition according to the present invention comprises at least one pharmacologically or cosmetologically acceptable surfactant which does not interact with the active ingredient, preferably present in the continuous phase of the emulsion.

Thus, one or more high HLB agents (15-16, for example) are incorporated into the hydrophilic phase of the emulsion in order to prepare an O / W emulsion and may contribute to the solubilization of the active principle incorporated in the hydrophilic phase. .

Similarly, one or more low HLB surfactants (5-6) are incorporated into the lipophilic phase of the emulsion to prepare an A / O emulsion and may contribute to the solubilization of the active principle in the lipophilic phase.

The surfactants used in the present invention should be pharmacologically or cosmetologically acceptable and should not interact with the active ingredient. Generally, surfactants are incorporated prior to emulsification into the phase intended to form the continuous phase of the emulsion.

Non-limiting examples of high HLB nonionic surfactants include glycerol esters, polyoxyethylene glycol or polyoxypropylene glycol esters, sucrose and fatty acid esters, polyoxyethylenated sorbitan esters and ester-bound surfactants. oxide such as polyoxyethylene or polyoxypropylene alcohols.

Preferably, for carrying out oil-in-water emulsions according to the present invention, polyoxyethylene glycol esters such as PEG 10 O-stearate (Arlacel® 165) or polyoxyethylenated alcohols such as Ceteareth-20 (Eumulgin®) are used. B2).

Non-limiting examples of low HLB nonionic surfactants include glycol esters, sorbitan esters, polyoxyethylenated alcohols.

Preferably, for carrying out water-in-oil type emulsions according to the present invention, sorbitan esters such as sorbitan laurate, sorbitan oleate, sorbitan stearate are used.

Non-limiting examples of silicone surfactants which allow formulating silicone emulsions, in particular water / silicone or glycol / silicone, include surfactants:

- of a methicone polyalkyl-type copolyols (optionally cross-linked oxyalkylenated methylsiloxane polyalkyls) containing saturated or unsaturated linear or branched C6 to C20 alkyl chains, a polyoxyethylene unit of 1 to 50 OE (ethylene oxide) and / or a polyoxypropylene unit of 1 to 50 OP (propylene oxide) and

- of an oxyalkylenated methylsiloxane dimethyl polyalkyl type containing: saturated or unsaturated, straight or branched C6 to C20 alkyl chains, a 1 to 50 OE polyoxyethylene moiety and / or a 1 to 50 OP polyoxypropylene moiety.

Advantageously, therefore, the allyldimethicone copolyols such as Abil EM-90, or the mixture of dimethicone copolyol and cyclomethicone sold by Dow Corning under the name 3235C Formulation Aid, the laurylmethicone copolyol sold under the name Emulsifier, will be used as silicone emulsifiers. 10 by Dow Corning, or mixtures based on a silicone polymer such as cetyl dimethicone copolyol with polyglyceryl-4 isostearate and hexyl laurate sold under the name of Abil WE09 by Goldschmidt, - Goldschmidt's Abil EM 97 (Dimethicone copolyol & cyclomethicone), Wacker Wacker SPG 128 VP (cyclomethicone and methoxy glycosyl octyldimethicone), Silwax WD-IS (Dimethicone copolyol isostearate). Non-polymeric siliconated emulsifiers such as siloxane mono or polyalkyl esters, for example Lambent's Silwax S (Dimethiconol stearate), or carboxylic acid carboxylic acid esters such as polyhydroxylated PEG alkyl esters, for example Uniqema's Arlacel P 135 (PEG), may also be used. -30 dipolihydroxystearate.

The formulation of emulsions in a pharmaceutical or cosmetic composition utilizes the usual techniques known to the skilled artisan in the field of formulation and galenics.

The composition according to the present invention is preferably suitable for topical application to the skin, pheromones and / or mucous membranes. The composition comprises an amount of active ingredient sufficient to achieve the desired effect.

Other compounds may be added to modulate skin penetration, to improve or decrease it.

Among these additional compounds that modulate the skin penetration of the active ingredient, for example, hydrophilic absorption promoters, lipophilic absorption promoters and agents that limit skin penetration are retained by retaining the molecule.

Hydrophilic absorption promoters include, for example, Propylene glycol, Transcutol, DMSO1, ethanol, N-methyl pyrrolidone, and preferably Propylene glycol.

Lipophilic absorption promoters include, for example, oleic acid, oleyl alcohol, oleyl oleate, oleyl erucate, macadamia oil or alpha-bisabolol, terpenes, azone, and preferably oleic acid.

Among the agents that limit the penetration of the active ingredient, for example, polyethylene glycols, and preferably PEG 400, are mentioned. These compounds, by their lattice structure, are known to retain certain molecules in this lattice and to brake their properties. release of the mesh to the target tissue.

The present invention may further comprise any additive commonly used in the cosmetic or pharmaceutical field, such as sequestering agents, wetting agents, adhesives, spreading agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, pigments, dyes, bases. or usual mineral or organic acids, essential oils, cosmetic actives, moisturizers, vitamins, essential fatty acids and / or sphingolipids

Of course, these or any complementary compounds, and / or their amount, are chosen such that the advantageous properties of the emulsion are not, or are not substantially altered.

Fabrication of the Composition The present invention also relates to a process for manufacturing a cosmetic or pharmaceutical composition as described above. However, two different processes can be distinguished according to the sensitivity of the active principle to temperature. By non-temperature sensitive is meant an active principle that withstands temperatures between 40 and 80 ° C without undergoing physical and / or chemical degradation.

Case A

In the case of a non-temperature sensitive active ingredient, it may be heated with the other constituents of the different phases. The process steps are as follows:

(i) mixing said active ingredient with at least one hydrophilic solvent at a temperature of 40 to 80 ° C to obtain a hydrophilic phase in which the active ingredient is present in solubilized form;

ii) mixing said active ingredient with at least one lipophilic solvent at a temperature of 40 to 80 ° C to obtain a lipophilic phase in which the active ingredient is present in solubilized form;

iii) mixing the hydrophilic phase obtained in i) with the lipophilic phase obtained in ii).

Preferably, the process comprises at the end of step ii) the addition of at least one further lipophilic compound to said lipophilic phase.

That case thus comprises the following steps:

(i) mixing said active ingredient with at least one hydrophilic solvent at a temperature of 40 to 80 ° C to obtain a hydrophilic phase in which the active ingredient is present in solubilized form;

ii) mixing said active ingredient with at least one lipophilic solvent at a temperature of 40 to 80 ° C to obtain a lipophilic active phase in which the active ingredient is present in solubilized form, and then mixing said phase. activates lipophilic with at least one other lipophilic compound to obtain a lipophilic phase; iii) mixing at least one hydrophilic phase obtained in i) with at least one lipophilic phase obtained in ii).

Advantageously, the process according to the present invention comprises the addition of at least one suitable HLB surfactant during step i) or step ii). A high HLB surfactant will be introduced into the hydrophilic phase, while a low HLB surfactant will be introduced into the lipophilic phase.

Thus, preferably, the composition preparation process according to the present invention comprises the following steps:

1 - Preparation of the hydrophilic phase:

a) Weigh the water and heat preferably between 60 and 80 ° C under slight agitation.

(b) - Add the active ingredient, preservative, chelating agent and pH adjuster and, if applicable, the high HLB surfactant and shake until complete solubilization of these compounds.

c) Incorporating the thickening agent and stirring preferably from 20 to 40 minutes at a temperature of 60 to 80 ° C, preferably at a temperature of 75 ° C.

d) - Then add the emulsion stabilizing agent (s) and allow to stir until complete solubilization.

2 - Preparation of the lipophilic phase:

(a) - Weigh all constituents of the lipophilic phase (with the exception of the active principle) and, if the high HLB surfactant is not incorporated into the hydrophilic phase, the low HLB surfactant, and preferably heat between 60 and 80 ° C under stirring until a homogeneous phase is achieved.

b) - The active ingredient, in its proportion intended for this phase, is then added to the lipophilic phase left under stirring until complete solubilization.

In a preferred mode of the process according to the present invention, the active ingredient is solubilized prior to performing step a) above in a lipophilic solvent of the active ingredient in order to obtain a mixture comprising the active principle. Step b) then consists of adding this mixture comprising the active principle in its proportion intended for this phase to the lipophilic phase left under stirring until complete solubilization.

3 - Emulsification:

Pour the hydrophilic phase into the lipophilic phase and emulsify under high agitation for a period of 5 to 20 minutes, preferably 10 minutes.

Process B

In the case of a temperature-sensitive active ingredient, the process should be modified to avoid heating the active ingredient to temperatures above 40 ° C as much as possible. When heating steps are required, for example in order to make solid constituent liquids at room temperature, the contact time of the active ingredient with the phase above 40 ° C will be reduced to a minimum. The process steps are as follows:

i) mixing said active ingredient with at least one hydrophilic solvent at a temperature below 40 ° C to obtain a hydrophilic active phase in which the active ingredient is present in solubilized form;

ii) preparing a hydrophilic inactive phase by heating at least one other hydrophilic compound at a temperature of 40 to 80 ° C;

iii) mixing said active ingredient with at least one lipophilic solvent at a temperature of less than 40 ° C to obtain a lipophilic phase in which the active ingredient is present in solubilized form; iv) mixing the hydrophilic inactive phase obtained in ii) with the lipophilic phase obtained in iii) at a temperature of approximately 50 to 60 ° C to obtain an emulsion;

v) cooling the emulsion obtained in iv) to a temperature of 30 to 45 ° C;

vi) mixing said emulsion obtained in v) with said hydrophilic active phase obtained in i), at a temperature between 30 and 45 ° C.

Advantageously, the process according to the present invention comprises the addition of at least one suitable HLB surfactant during step ii) (preparation of hydrophilic non-active phase) or step iii) (preparation of lipophilic phase).

Preferably, the process comprises the following steps:

i) mixing said active ingredient with at least one hydrophilic solvent at a temperature of less than 40 ° C to obtain a hydrophilic active phase in which the active ingredient is present in solubilized form;

ii) preparing a hydrophilic inactive phase by heating at least one other hydrophilic compound at a temperature of 40 to 80 ° C;

iii) mixing said active ingredient with at least one lipophilic solvent at a temperature below 40 ° C to obtain a lipophilic active phase in which the active ingredient is present in solubilized form;

iv) preparing a lipophilic inactive phase by heating at least one other lipophilic compound at a temperature of 40 to 80 ° C;

(v) cooling the lipophilic non-active phase obtained in (iv) to a temperature of not more than 40 ° C;

vi) mixing the cooled lipophilic non-active phase obtained in v) with the lipophilic active phase obtained in iii); vii) mixing the hydrophilic inactive phase obtained in ii) with the lipophilic phase obtained in vi) at a temperature of approximately 50 to 60 ° C to obtain an emulsion;

viii) cooling the emulsion obtained in vii) to a temperature of 30 to 45 ° C;

ix) mixing said emulsion obtained in viii) with said hydrophilic active phase obtained in i) at a temperature comprised between 30 and 45 ° C.

Advantageously, the process according to the present invention comprises the addition of at least one appropriate HLB surfactant during step ii) (preparation of the hydrophilic non-active phase) or step iv) (preparation of the lipophilic non-active phase). A high HLB surfactant will be introduced into the hydrophilic phase, while a low HLB surfactant will be introduced into the lipophilic phase.

Thus, preferably, the composition preparation process according to the present invention comprises the following steps:

1 - Preparation of the hydrophilic phase:

a) Weigh the water and heat preferably between 60 and 80 ° C under slight agitation.

(b) - Add the preservative, chelating agent and pH adjuster e. if applicable, the HLB surfactant is high, and stir until complete solubilization of these compounds.

c) Incorporating the thickening agent and stirring preferably from 20 to 40 minutes at a temperature of 60 to 80 ° C, preferably at a temperature of 75 ° C.

d) - Then add the emulsion stabilizing agent (s) and allow to stir until complete solubilization.

e) - In addition, solubilize the proportion of active ingredient intended for the hydrophilic phase in a glycol / antioxidant mixture at a temperature of less than 40 ° C, preferably room temperature.

2 - Preparation of the lipophilic phase:

a) - Identify the lipophilic phase constituents that are liquid at room temperature and the solids that need to be melted.

b) Identify at least one of the constituents of the liquid lipophilic phase at room temperature and solvent of the active principle and solubilize the active principle therein.

c) Weigh all other constituents of the lipophilic phase and, if the high HLB surfactant is not incorporated into the hydrophilic phase, the low HLB surfactant, and preferably heat to a temperature necessary to melt the solid constituents, ie. at 60 to 80 ° C under stirring until a homogeneous phase is obtained.

Preferably, let the phase temperature cool to maximum before the next step.

d) - Add the active mixture / lipophilic ingredient to this stirred lipophilic phase until a new homogeneous phase is achieved minimizing the contact time of the active ingredient with the potentially elevated temperature of the lipophilic phase. Rapidly emulsify and cool down.

3 - Emulsification:

a) Pour the hydrophilic phase obtained at the end of step d) of the preparation of the hydrophilic phase into the lipophilic phase and emulsify under strong agitation for a period of 5 to 20 minutes, preferably for 10 minutes at a temperature of approximately 50 to 60 ° C. ° C.

b) Cool slowly while maintaining the emulsion under moderate agitation.

(c) At a temperature of 30 to 45 ° C, preferably around 35-40 ° C, incorporate the active ingredient intended for the hydrophilic phase previously solubilised in the glycol / antioxidant mixture (preparation step (e)). hydrophilic phase) in the emulsion and keep stirring until the emulsion returns to room temperature.

In the above text, stirring of solutions or emulsions according to the present disclosure may be performed with conventional apparatus such as, for example, a Rayneri apparatus.

By gentle agitation according to the present invention is meant agitation obtained from a Rayneri apparatus of a value of less than 300 rpm.

By moderate agitation according to the present invention is meant agitation obtained from a Rayneri apparatus comprised between 301 and 700 rpm.

By strong agitation according to the present invention is meant agitation obtained from a Rayneri apparatus comprised between 701 and 1500 rpm.

By room temperature is meant a temperature of from 20 to 30 ° C, preferably from 23 to 27 ° C, preferably a temperature of 25 ° C.

According to a particularly preferred embodiment, the composition prepared according to the process of the present invention is an O / W oil-in-water emulsion, in other words, an emulsion in which said first phase according to the description. It is a lipophilic phase dispersed in a second continuous, hydrophilic phase.

Cosmetic or Pharmaceutical Applications

The compositions according to the present invention may be used for a pharmaceutical or cosmetic application. They are preferably in a form suitable for topical use, for example in the form of cream, foam, spray, aerosol or any form of administration compatible with the claimed formulation.

Preferably, the composition according to the present invention contains vitamin D or a vitamin D derivative and is applicable in dermatology, for example, in the following applications, preferably in the treatment of psoriasis.

This composition is particularly appropriate:

1) to treat dermatological disorders linked to a disorder of the differentiation or proliferation of keratinocytes or sebocytes, in particular to treat vulgar, comedonian, polymorphic, rosacea, nodulocystic acne, conglobata acne, acne senis, acne secondary diseases such as solar acne, medication or professional acne;

2) to treat keratinization disorders, especially ichthyosis, ichthyosiform states, Darrier disease, palmoplantar keratoderma, leukoplakia and leukosiform states, cutaneous or mucous (oral) lichen;

3) to treat other dermatological disorders linked to a keratinization disorder with an inflammatory and / or immunoallergic component and, in particular, all forms of psoriasis, whether cutaneous, mucous or nail, and even psoriasis rheumatism, or atopy. such as eczema or respiratory atopy or gingival hypertrophy;

4) to treat certain inflammatory skin disorders that do not have keratinization disorders, such as atopic eczama and contact allergies.

5) to treat all dermal or epidermal proliferation whether benign or malignant, whether or not of viral origin such as vulgar warts, flat warts and verruciform epidermodysplasia, oral or flowery papillomatosis, T lymphoma, and proliferations may be induced by ultraviolets, especially in the case of basal and spinocellular epitheliomas;

6) to treat other dermatological disorders such as bullous dermatoses and collagen diseases;

7) to prevent or treat the signs of skin aging, whether photoinduced or chronological or to reduce actinic pigmentation and keratoses, or any skin conditions associated with chronological or actinic aging;

8) to prevent or treat healing disorders or to prevent and repair stretch marks;

9) to combat sebaceous function disorders such as acne hyperborrhea, simple hyperborrhea or seborrheic eczema;

10) to treat certain ophthalmic disorders, in particular corneopathies;

11) for the treatment or prevention of cancerous or precancerous conditions of skin cancers or not which present or may be induced to present vitamin D receptors such as, but not limited to, breast cancer, leukemia, syndromes myelodysplastic and lymphomas, carcinomas of cells in the malpingeal epithelium and gastrointestinal cancers, melanomas, and osteosarcoma;

12) to treat inflammatory conditions such as arthritis or rheumatoid polyarthritis;

13) for the treatment of any condition of viral origin at the cutaneous or general level;

14) for the prevention of alopecia of different origins, in particular alopecia due to chemotherapy or radiation;

15) for the treatment of general or immunological dermatological disorders;

16) for the treatment of immunological disorders such as autoimmune diseases (such as, but not limited to, type 1 sugary diabetes, plaque sclerosis, lupus and lupus disorders, asthma, glomerulonephritis, etc.), selective immune-like (AIDS-like) dysfunctions and prevention of immune rejection, such as graft rejections (eg kidney, heart, bone marrow, liver, pancreatic islets or the entire pancreas, skin, etc.) or the prevention of graft versus host disease;

17) for the treatment of endocrine disorders which may be treated by vitamin D analogues such as those which advantageously modulate hormone secretion, for example by increasing insulin secretion or by selective suppression of parathyroid hormone secretion (for example, in insufficiency of parathyroid hormone secretion). renal failure and secondary hyperparoidia);

18) for the treatment of conditions characterized by abnormal intracellular calcium management; and

19) for the treatment and / or prevention of vitamin D deficiencies and other disorders of mineral homeostasis such as plasma and bone such as rachidism, osteomalacia, osteoporosis, and in particular for menopausal women, renal osteodystrophy, disorders of parathyroid function.

A particular object of the present invention is therefore an emulsion comprising a hydrophilic and lipophilic phase of vitamin D or an analogue or derivative of vitamin D, i.e. preferably (4E, 6E) -7- [3- (3,4-Bishydroxymethyl-benzyloxy) -phenyl] -3-ethyl-nona-4,6-dien-3-ol which is present and in solubilized form at each of these stages.

An object of the present invention relates more particularly to an emulsion comprising a glycolic or hydroglycolic phase and a lipophilic phase, and (4E, 6E) -7- [3- (3,4-Bishydroxymethylbenzyloxy) -phenyl] - 3-ethyl-nona-4,6-dien-3-ol is present in solubilized form in each of these phases.

Another object of the present invention is a pharmaceutical or cosmetic composition for topical use comprising such an emulsion.

Another object of the present invention is the use of a composition as defined above, in particular an emulsion, for the preparation of a medicament for the treatment of skin disorders, in particular psoriasis.

In fact, vitamin D and its analogs or derivatives limit the excessive production of skin cells on the affected surfaces and have proven advantages for treating this condition, which is characterized in particular by the presence of thick, scaly and dry lesions.

The following examples illustrate the present invention without, however, limiting its scope.

In Examples 1 and 2, the amounts of constituents entering the composition of the formulations are expressed as a percentage by weight relative to the total weight of the composition.

Examples Example 1

Manufacturing Process Usable for Examples 2 or 3) 1 - Preparation of the hydrophilic phase:

- Weigh the water and heat to 75 ° C under slight agitation.

- Add EDTA, sodium hydrogen phosphate and methylparaben and shake gently until complete solubilization.

Incorporate Veegum K and shake gently for 30 minutes at 75 ° C.

Then add Keltrol T and leave to stir until complete solubilization. 2 - LIPOPHYLE PHASE PREPARATION:

- Weigh all constituents of the lipophilic phase (except for (4E, 6E) -7- [3- (3,4-bis-hydroxymethyl-benzyloxy) -phenyl] -3-ethyl-nona-4,6-diene). 3-ol) and heat to 75 ° C under moderate stirring until a homogeneous phase is obtained.

- Add the (4E, 6E) -7- [3- (3,4-bis-hydroxymethyl-benzyloxy) -phenyl] -3-ethyl-nona-4,6-dien-3-ol for this step and allow under stirring until complete solubilization.

3 - EMULSIFICATION:

- Pour the hydrophilic phase into the lipophilic phase and emulsify under strong

stirring (1200 rpm) for 10 minutes at a temperature of approximately 60 ° C.

- Slowly cool while maintaining moderate agitation at 700 rpm.

- At 35-40 ° C, incorporate (4E, 6E) -7- [3- (3,4-bis-hydroxymethylbenzyloxy) -phenyl] -3-ethyl-nona-4,6-diene. 3-ol previously solubilized in the glycol / BHA1 mixture in the emulsion and keep stirring until the emulsion returns to room temperature.

Example 2

O / W EMULSION

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O / W emulsion

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The examples cited above illustrate the interest of mixed solubilization.

In fact, the preparation of a 0.3% (4E, 6E) -7- [3- (3,4-bis-hydroxymethyl-benzyloxy) -phenyl] -3-ethyl-nona-4,6- dien-3-ol became possible only thanks to a mixed solubilization of the molecule: a fraction in the hydrophilic phase and a fraction in the lipophilic phase.

Single-phase (4E, 6E) -7- [3- (3,4-bis-hydroxymethyl-benzyloxy) -phenyl] -3-ethyl-nona-4,6-dien-3-ol solubilization assays hydrophilic phase or lipophilic phase) did not provide a physically stable emulsion over time; (4E, 6E) -7- [3- (3,4-bis-hydroxymethyl-benzyloxy) -phenyl] -3-ethyl-nona-4,6-dien-3-ol crystalline growth phenomena appeared from the first month of storage at 4 ° C. In contrast, mixed solubilization allowed good emulsion physical stability and the absence of crystalline growth after 3 months of storage at A ° C.

Claims (19)

PHARMACEUTICAL OR COSMETIC COMPOSITION, characterized in that it comprises: - at least one hydrophilic phase, - at least one lipophilic phase, comprising at least one lipophilic solvent, - and at least one active principle, in which the coefficient yogarithm The active ingredient sharing composition is comprised between 2 and 6, and wherein the active ingredient is present in solubilized form in at least one hydrophilic phase and at least in the lipophilic solvent of the lipophilic phase. Composition according to Claim 1, characterized in that said hydrophilic phase comprises the active ingredient solubilized in at least one hydrophilic solvent and at least one other hydrophilic compound. Composition according to Claim 1 or 2, characterized in that the composition is an emulsion. Composition according to one of Claims 1 to 3, characterized in that it comprises a hydrophilic phase and a lipophilic phase. Composition according to one of Claims 1 to 4, characterized in that at least one hydrophilic phase is a glycolic or hydroglycolic phase. Composition according to one of Claims 1 to 5, characterized in that the active ingredient is chosen from the group consisting of steroidal, antifungal, antiparasitic anti-inflammatory agents, nuclear receptor modulators and sex steroids. Composition according to Claim 6, characterized in that the active ingredient is a corticosteroid. Composition according to Claim 6, characterized in that the active ingredient is a retinoid. Composition according to Claim 6, characterized in that the active ingredient is a derivative of vitamin D. Composition according to Claim 6, characterized in that the active ingredient is (4E, 6E) -7- [3- (3,4-bis-hydroxymethyl-benzyloxy) -phenyl] -3-ethyl. -ona-4,6-dien-3-ol. Composition according to one of Claims 1 to 10, characterized in that it further comprises at least one pharmacologically or cosmetologically acceptable surfactant. Composition according to one of Claims 1 to 11, characterized in that it is in a form suitable for topical use. Use of a composition as defined in one of claims 1 to 12, characterized in that it is for the preparation of a medicament for the treatment of psoriasis. Process for the manufacture of a composition as defined in claims 1 to 12, characterized in that it comprises the following steps: (i) mixing said active ingredient with at least one hydrophilic solvent at a temperature between 40 and 80 ° C. C to obtain a hydrophilic phase in which the active ingredient is present in solubilized form; (ii) mixing said active ingredient with at least one lipophilic solvent at a temperature of 40 to 80 ° C to obtain a lipophilic phase in which the active ingredient is present in solubilized form; (iii) mixing the hydrophilic phase obtained in (i) with the lipophilic phase obtained in (ii). Process according to Claim 14, characterized in that it comprises at the end of step (ii) the addition of at least one other lipophilic compound to said lipophilic phase. Process according to Claim 14 or 15, characterized in that at least one suitable HLB surfactant is added during step (i) or step (ii). Process for the manufacture of a composition as defined in claims 2 to 12, characterized in that it comprises the following steps: (i) mixing said active ingredient with at least one hydrophilic solvent at a temperature below 40 ° C; in order to obtain a hydrophilic active phase in which the active principle is present in solubilized form; (ii) preparing a hydrophilic inactive phase by heating at least one other hydrophilic compound to a temperature of 40 to 80 ° C; (iii) mixing said active ingredient with at least one lipophilic solvent at a temperature of less than 40 ° C to obtain a lipophilic phase in which the active ingredient is present in solubilized form; (iv) mixing the hydrophilic inactive phase obtained in (ii) with the lipophilic phase obtained in (iii) at a temperature of approximately 50 to 60 ° C to obtain an emulsion; (v) cooling the emulsion obtained in (iv) to a temperature of 30 to 45 ° C; (vi) mixing said emulsion obtained in (v) with said hydrophilic active phase obtained in (i) at a temperature comprised between 30 and 45 ° C. Process for the manufacture of a composition as defined in claims 1 to 12, characterized in that it comprises the following steps: (i) mixing said active ingredient with at least one hydrophilic solvent at a temperature of less than 40 ° C; in order to obtain a hydrophilic active phase in which the active principle is present in solubilized form; (ii) preparing a hydrophilic inactive phase by heating at least one other hydrophilic compound to a temperature of 40 to 80 ° C; (iii) mixing said active ingredient with at least one lipophilic solvent at a temperature below 40 ° C to obtain a lipophilic active phase in which the active ingredient is present in solubilized form; (iv) preparing a lipophilic inactive phase by heating at least one other lipophilic compound at a temperature of 40 to 80 ° C; (v) cooling the lipophilic non-active phase obtained in (iv) to a temperature of at most 40 ° C; (vi) mixing at least one cooled non-active lipophilic phase obtained in (v) with the lipophilic active phase obtained in (iii); (vii) mixing the hydrophilic inactive phase obtained in (ii) with the lipophilic phase obtained in (vi) at a temperature of approximately 50 to 60 ° C to obtain an emulsion; (viii) cooling the emulsion obtained in (vii) to a temperature of 30 to 45 ° C; (ix) mixing said emulsion obtained in (viii) with said hydrophilic active phase obtained in (i) at a temperature between 30 and -45 ° C. Process according to Claim 18, characterized in that at least one suitable HLB surfactant is added during step (ii) or step (iv).